Immobilized Coupling Reagents: Synthesis of Amides/Peptides (original) (raw)
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Benzhydrylamine linker grafting: a strategy for the improved synthesis of C‐terminal peptide amides
Journal of Peptide Science, 2010
The standard p‐MBHA resin used during Boc‐chemistry synthesis of peptides carrying C‐terminal carboxamides is compromised by batch‐to‐batch variations in its performance. This can cause artificially ‘difficult’ couplings during peptide chain assembly, which may ultimately lead to failed syntheses given the inability to achieve acceptable coupling yields. To overcome these problems, we have developed a new approach by grafting a functionalized benzhydrylamine linker onto well‐characterized and well‐performing PAM resins. We combine optimized Boc‐chemistry, high‐performing PAM resins and new benzhydrylamine‐based linkers to achieve improved syntheses of peptide amides. Here we present the synthesis of two new benzhydrylamine linkers and their attachment to selected PAM resins. This novel solid support was evaluated through the synthesis of selected ‘difficult’ conotoxins and monitoring the coupling efficiency using quantitative ninhydrin assay. The results show a superior performance ...
Amide bond formation: beyond the myth of coupling reagents
Amide bond formation is a fundamentally important reaction in organic synthesis, and is typically mediated by one of a myriad of so-called coupling reagents. This critical review is focussed on the most recently developed coupling reagents with particular attention paid to the pros and cons of the plethora of ''acronym'' based reagents. It aims to demystify the process allowing the chemist to make a sensible and educated choice when carrying out an amide coupling reaction (179 references).
Journal of the American Chemical Society, 1998
Peptide targets for synthesis are often desired with C-terminal end groups other than the more usual acid and amide functionalities. Relatively few routes exist for synthesis of C-terminal-modified peptidessincluding cyclic peptidessby either solution or solid-phase methods, and known routes are often limited in terms of ease and generality. We describe here a novel Backbone Amide Linker (BAL) approach, whereby the growing peptide is anchored through a backbone nitrogen, thus allowing considerable flexibility in management of the termini. Initial efforts on BAL have adapted the chemistry of the tris(alkoxy)benzylamide system exploited previously with PAL anchors. Aldehyde precursors to PAL, e.g. 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid, were reductively coupled to the R-amine of the prospective C-terminal amino acid, which was blocked as a tert-butyl, allyl, or methyl ester, or to the appropriately protected C-terminal-modified amino acid derivative. These reductive aminations were carried out either in solution or on the solid phase, and occurred without racemization. The secondary amine intermediates resulting from solution amination were converted to the 9-fluorenylmethoxycarbonyl (Fmoc)-protected preformed handle derivatives, which were then attached to poly-(ethylene glycol)-polystyrene (PEG-PS) graft or copoly(styrene-1% divinylbenzene) (PS) supports and used to assemble peptides by standard Fmoc solid-phase chemistry. Alternatively, BAL anchors formed by onresin reductive amination were applied directly. Conditions were optimized to achieve near-quantitative acylation at the difficult step to introduce the penultimate residue, and a side reaction involving diketopiperazine formation under some circumstances was prevented by a modified protocol for N R-protection of the second residue/ introduction of the third residue. Examples are provided for the syntheses in high yields and purities of representative peptide acids, alcohols, N,N-dialkylamides, aldehydes, esters, and head-to-tail cyclic peptides. These methodologies avoid postsynthetic solution-phase transformations and are ripe for further extension.
A new reagent and its polymer-supported variant for the amidination of amines
Tetrahedron Letters, 2002
New reagents for the high yielding amidination of primary and secondary amines are described. By attaching a benzyl substituent to the 3,5-dimethyl-1H-pyrazole-1-carboxamidine ring, a reagent 1 is obtained which allows easy work-up after amidination because of solubility of byproducts in organic solvents. In addition, the polystyrene-bound analogue 2 was prepared which allows amidination of various amines with high purity.
Ubiquitousness of amide and ester functionality makes coupling reactions extremely important. Although numerous coupling reagents are available, methods of preparation of the common and efficient reagents are cumbersome. Those reagents generate a substantial amount of chemical waste and lack recyclability. Ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino)acetate (o-NosylOXY), the first member of a new generation of coupling reagents, produces byproducts that can be easily recovered and reused for the synthesis of the same reagent, making the method more environmentally friendly and cost-effective. The synthesis of amides, hydroxamates, peptides, and esters using this reagent is described. The synthesis of the difficult sequences, for example, the islet amyloid polypeptide (22−27) fragment (with a C-terminal Gly, H-Asn-Phe-Gly-Ala-Ile-Leu-Gly-NH 2) and acyl carrier protein (65−74) fragment (H-Val-Gln-Ala-Ala-Ile-Asp-Tyr-Ile-Asn-Gly-OH), following the solid-phase peptide synthesis (SPPS) protocol and Amyloid β (39−42) peptide (Boc-Val-Val-IIe-Ala-OMe), following solution-phase strategy is demonstrated. Remarkable improvement is noticed with respect to reaction time, yield, and retention of stereochemistry. A mechanistic investigation and recyclability are also described.
Journal of the American Chemical Society, 1998
Peptide targets for synthesis are often desired with C-terminal end groups other than the more usual acid and amide functionalities. Relatively few routes exist for synthesis of C-terminal-modified peptidessincluding cyclic peptidessby either solution or solid-phase methods, and known routes are often limited in terms of ease and generality. We describe here a novel Backbone Amide Linker (BAL) approach, whereby the growing peptide is anchored through a backbone nitrogen, thus allowing considerable flexibility in management of the termini. Initial efforts on BAL have adapted the chemistry of the tris(alkoxy)benzylamide system exploited previously with PAL anchors. Aldehyde precursors to PAL, e.g. 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid, were reductively coupled to the R-amine of the prospective C-terminal amino acid, which was blocked as a tert-butyl, allyl, or methyl ester, or to the appropriately protected C-terminal-modified amino acid derivative. These reductive aminations were carried out either in solution or on the solid phase, and occurred without racemization. The secondary amine intermediates resulting from solution amination were converted to the 9-fluorenylmethoxycarbonyl (Fmoc)-protected preformed handle derivatives, which were then attached to poly-(ethylene glycol)-polystyrene (PEG-PS) graft or copoly(styrene-1% divinylbenzene) (PS) supports and used to assemble peptides by standard Fmoc solid-phase chemistry. Alternatively, BAL anchors formed by onresin reductive amination were applied directly. Conditions were optimized to achieve near-quantitative acylation at the difficult step to introduce the penultimate residue, and a side reaction involving diketopiperazine formation under some circumstances was prevented by a modified protocol for N R-protection of the second residue/ introduction of the third residue. Examples are provided for the syntheses in high yields and purities of representative peptide acids, alcohols, N,N-dialkylamides, aldehydes, esters, and head-to-tail cyclic peptides. These methodologies avoid postsynthetic solution-phase transformations and are ripe for further extension.
Recent development in peptide coupling reagents
Journal of Saudi Chemical Society, 2011
Two decades of domination of benzotriazole-based chemistry stimulated the progress in peptide synthesis to a high level of effectiveness. However, the growing need for new and more complex peptide structures, particularly for biomedical studies and, very recently, for the large-scale production of peptides as drugs, required manufacturing peptide products by efficient synthetic strategies, at reasonably low prices. Therefore, the search for new, more versatile and low-cost reagents becomes a great challenge. Several comprehensive review articles summarized the great effort undertaken, but up to now, no versatile coupling reagent useful for both amide and ester bond formation, as well as for solution and solid-phase peptide synthesis has been yet developed. The most-widely used coupling reagents are carbodiimides on one hand and phosphonium and aminium salts on the other. Herein in this review article, we summarized the recent development in peptide coupling reagents during the last two decades.